- Structure-Based Optimization and Discovery of M3258, a Specific Inhibitor of the Immunoproteasome Subunit LMP7 (β5i)
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Proteasomes are broadly expressed key components of the ubiquitin-dependent protein degradation pathway containing catalytically active subunits (β1, β2, and β5). LMP7 (β5i) is a subunit of the immunoproteasome, an inducible isoform that is predominantly expressed in hematopoietic cells. Clinically effective pan-proteasome inhibitors for the treatment of multiple myeloma (MM) nonselectively target LMP7 and other subunits of the constitutive proteasome and immunoproteasome with comparable potency, which can limit the therapeutic applicability of these drugs. Here, we describe the discovery and structure-based hit optimization of novel amido boronic acids, which selectively inhibit LMP7 while sparing all other subunits. The exploitation of structural differences between the proteasome subunits culminated in the identification of the highly potent, exquisitely selective, and orally available LMP7 inhibitor 50 (M3258). Based on the strong antitumor activity observed with M3258 in MM models and a favorable preclinical data package, a phase I clinical trial was initiated in relapsed/refractory MM patients.
- Klein, Markus,Busch, Michael,Friese-Hamim, Manja,Crosignani, Stefano,Fuchss, Thomas,Musil, Djordje,Rohdich, Felix,Sanderson, Michael P.,Seenisamy, Jeyaprakashnarayanan,Walter-Bausch, Gina,Zanelli, Ugo,Hewitt, Philip,Esdar, Christina,Schadt, Oliver
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supporting information
p. 10230 - 10245
(2021/07/26)
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- Structure-based development of (1-(3′-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- And Serine-β-lactamases
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The emergence and spread of bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2′S)-(1-(3′-mercapto-2′-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new, more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2 and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes.
- Wang, Yao-Ling,Liu, Sha,Yu, Zhu-Jun,Lei, Yuan,Huang, Meng-Yi,Yan, Yu-Hang,Ma, Qiang,Zheng, Yang,Deng, Hui,Sun, Ying,Wu, Chengyong,Yu, Yamei,Chen, Qiang,Wang, Zhenling,Wu, Yong,Li, Guo-Bo
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p. 7160 - 7184
(2019/08/28)
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- Mercapto-amide boronic acid derivative and application thereof as MBL (metal beta-lactamase) and/or SBL (serine beta-lactamase) inhibitor
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The invention provides a compound of a formula (I) shown in the specification, or a conformational isomer, or an optical isomer or a pharmaceutically acceptable salt thereof. The compound of the formula (I) shown in the specification has excellent broad-spectrum inhibitory activity on MBL (metal beta-lactamase) and/or SBL (serine beta-lactamase), and can be used for preparing MBL and/or SBL inhibitors. Moreover, the compound disclosed by the invention has excellent antibacterial activity on multiple drug-resistant bacteria and is capable of reversing drug resistance of carbapenem drug-resistant bacteria, and the antibacterial effect of the compound is prior to those of positive control products such as L-captopril and tazobactam. The compound disclosed by the invention has very great potential in preparation of MBL/SBL dual inhibitors and medicines reversing drug resistance of carbapenem drug-resistance bacteria.
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Paragraph 0114; 0115; 0120-0122; 0138-0140
(2019/09/14)
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- Virtues of Volatility: A Facile Transesterification Approach to Boronic Acids
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Boronic acids are an increasingly important compound class for many applications, including C-C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic and inefficient step in boronic acid syntheses. We describe an approach that highly facilitates this transformation by leveraging the volatility of methylboronic acid and its diol esters. The method is performed under mild conditions, provides high yields, and eliminates cumbersome and problematic purification steps.
- Hinkes, Stefan P.A.,Klein, Christian D.P.
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p. 3048 - 3052
(2019/05/10)
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- Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib
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A series of structurally novel proteasome inhibitors 1–12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50 = 9.7 nM) to bortezomib (IC50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.
- Xu, Yulong,Yang, Xicheng,Chen, Yiyi,Chen, Hao,Sun, Huijiao,Li, Wei,Xie, Qiong,Yu, Linqian,Shao, Liming
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p. 2148 - 2152
(2018/05/25)
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- Boric acid compound used as 20S proteasome inhibitor, and preparation method thereof
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The invention relates to the fields of pharmaceutical chemistry and medicine therapeutics, concretely relates to new boric acid compounds, and a preparation method and a use thereof, and especially relates to a boric acid compound used as a 20S proteasome inhibitor, and a preparation method thereof. The invention also discloses a boric acid compound represented by formula I, and a preparation method thereof. A result of bioactive screening test shows that the compound prepared in the invention has a proteasome inhibition function, and can be further used for preparing medicines for treating proteasome correlated diseases.
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- Boric acid compounds, and preparation method and use thereof
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The invention relates to the fields of pharmaceutical chemistry and medicine therapeutics, concretely relates to a new boric acid compounds, and a preparation method and a use thereof, and especially relates to new substituted five-membered heterocyclic boric acid and substituted benzo five-membered boric acid compounds, and a preparation method thereof. A result of bioactive screening test of the substituted five-membered heterocyclic boric acid and substituted benzo five-membered boric acid compounds having a structure represented by a formula shown in the description shows that the compounds have a proteasome inhibition effect, and can be further used for preparing medicines for treating proteasome correlated diseases.
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Paragraph 0184; 0185; 0186
(2017/09/21)
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- Preparation of (1R)-(S)-pinane diol-1-amino-3-methyl-butane-1-borate and a salt thereof
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The invention discloses a method for preparing (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester and a salt thereof. The method for preparing (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester comprises step A and step B in the following synthetic route, wherein in the formula, X represents a halogen atom and M represents an alkali metal. (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester is subjected to a salt forming reaction with an organic acid or an inorganic aid, and an acidic salt of (1R)-(S)-pinanediol-1-amino-3-methylbutane-1-borate ester is obtained. The method of the invention can help to synthesize high-purity bortezomib or other boropeptide compounds in low cost, is accord with industrial production requirements and has practical value.
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- Proteasome inhibitor delanzomib for use in the treatment of lupus
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The present invention provides a method for treating lupus in a subject, comprising the step of administering to the subject Compound A.
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Page/Page column 15; 16
(2016/06/06)
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- PROTEASOME INHIBITORS AND PROCESSES FOR THEIR PREPARATION, PURIFICATION AND USE
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The invention provides boronic esters of Formula (I) wherein R1, R2, R3, and R4 are as described herein, and methods for the preparation and purification thereof.
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Page/Page column 107-108
(2011/08/04)
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- Synthesis, in vitro and in vivo biological evaluation, and comprehensive understanding of structure-activity relationships of dipeptidyl boronic acid proteasome inhibitors constructed from β-amino acids
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An extensive structure-activity relationship (SAR) study of 72 dipeptidyl boronic acid proteasome inhibitors constructed fromβ -amino acids is reported. SAR analysis revealed that bicyclic groups at the R1 position, 3-F substituents at the Rsu
- Zhu, Yongqiang,Wu, Gang,Zhu, Xinrong,Ma, Yuheng,Zhao, Xin,Li, Yuejie,Yuan, Yunxia,Yang, Jie,Yu, Sen,Shao, Feng,Lei, Meng
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p. 8619 - 8626
(2011/03/20)
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- Observations on the deprotection of pinanediol and pinacol boronate esters via fluorinated intermediates
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(Chemical Equation Presented) Methods for the deprotection of pinanediol and pinacol esters of various boronic acids via fluoroborane intermediates were evaluated. Treatment of the boronate esters with potassium hydrogen difluoride normally gives trifluor
- Inglis, Steven R.,Woon, Esther C. Y.,Thompson, Amber L.,Schofield, Christopher J.
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supporting information; experimental part
p. 468 - 471
(2010/03/25)
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- Synthesis, in vitro and in vivo biological evaluation, docking studies, and structure-activity relationship (SAR) discussion of dipeptidyl boronic acid proteasome inhibitors composed of β-amino acids
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A series of novel dipeptidyl boronic acid proteasome inhibitors composed of β-amino acids were synthesized, in vitro and in vivo biologically evaluated, and theoretically modeled for the first time. From the screened racemic compounds in enzyme, 4i was the most active. The IC50 value of its pure enantiomer 4q was 9.6 nM, 36-fold more active than its isomer 4p and as active as the marketed bortezomib in inhibiting human 20S proteasome. This candidate also showed good activities with IC50 values nearly less than 5 μM against several human solid and hematologic tumor cell lines. Safety evaluation in vivo with zebrafish and Sprague-Dawley (SD) rats showed that the candidate 4q was less toxic than bortezomib. Pharmacokinetic profiles suggested candidate 4q showed a more plasma exposure and longer half-life than bortezomib. Docking results indicated that 4q nearly interacted with 20S proteasome in a similar way as bortezomib.
- Zhu, Yongqiang,Zhu, Xinrong,Wu, Gang,Ma, Yuheng,Li, Yuejie,Zhao, Xin,Yuan, Yunxia,Yang, Jie,Yu, Sen,Shao, Feng,Li, Runtao,Ke, Yanrong,Lu, Aijun,Liu, Zhenming,Zhang, Liangren
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supporting information; scheme or table
p. 1990 - 1999
(2010/08/03)
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- Design, synthesis, biological evaluation, and Structure-Activity Relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, Part I: Comprehensive understanding of the SAR of α-amino acid boronates
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New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC50 values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC50 values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC50 value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.
- Zhu, Yongqiang,Zhao, Xin,Zhu, Xinrong,Wu, Gang,Li, Yuejie,Ma, Yuheng,Yuan, Yunxia,Yang, Jie,Hu, Yang,Ai, Li,Gao, Qingzhi
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supporting information; experimental part
p. 4192 - 4199
(2010/01/16)
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- Synthesis and biological evaluation of boron peptide analogues of Belactosin C as proteasome inhibitors
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A series of boron peptides 11, 13, 15 and 17 were designed and synthesized as proteasome inhibitors based on the structure of Belactosin C. Matteson homologation was a key step in the synthesis of the boron peptides. Compounds 11a and 13 showed significant inhibition of 20S proteasome chymotrypsin-like (β5) activity (IC50 = 0.28 and 0.51 μM, respectively). Furthermore, like PS-341, compound 11a increased the G2/M cell distribution. A biparametric cytofluorimetric analysis with FITC-labeled annexin V and propidium iodide showed induction of apoptosis by compound 11a at >1 μM concentrations of compound.
- Nakamura, Hiroyuki,Watanabe, Mizuyoshi,Ban, Hyun Seung,Nabeyama, Wataru,Asai, Akira
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scheme or table
p. 3220 - 3224
(2010/04/05)
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- Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer
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The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl] amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.
- Dorsey, Bruce D.,Iqbal, Mohamed,Chatterjee, Sankar,Menta, Ernesto,Bernardini, Raffaella,Bernareggi, Alberto,Cassarà, Paolo G.,D'Arasmo, Germano,Ferretti, Edmondo,De Munari, Sergio,Oliva, Ambrogio,Pezzoni, Gabriella,Allievi, Cecilia,Strepponi, Ivan,Ruggeri, Bruce,Ator, Mark A.,Williams, Michael,Mallamo, John P.
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p. 1068 - 1072
(2008/12/22)
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- Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases
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Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.
- Debaene, Fran?ois,Da Silva, Julien A.,Pianowski, Zbigniew,Duran, Fernando J.,Winssinger, Nicolas
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p. 6577 - 6586
(2008/02/05)
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- Proteasome inhibitors and methods of using the same
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.
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Page/Page column 30
(2008/06/13)
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- PROTEASOME INHIBITORS AND METHODS OF USING THE SAME
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
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Page/Page column 24
(2008/06/13)
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- PROTEASOME INHIBITORS AND METHODS OF USING THE SAME
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The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
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Page/Page column 54
(2008/06/13)
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- Identification of a potent and rapidly reversible inhibitor of the 20S-proteasome
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Synthesis and in vitro characterization of a novel, lactam boronic acid based, selective, and rapidly reversible inhibitor of the 20S-proteasome is presented. Synthesis and in vitro characterization of novel, lactam boronic acid based, selective, and rapi
- Purandare, Ashok V.,Wan, Honghe,Laing, Naomi,Benbatoul, Khalid,Vaccaro, Wayne,Poss, Michael A.
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p. 4701 - 4704
(2007/10/03)
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- P1 Phenethyl peptide boronic acid inhibitors of HCV NS3 protease
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A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin.
- Priestley,De Lucca, Indawati,Ghavimi, Bahman,Erickson-Viitanen, Susan,Decicco, Carl P.
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p. 3199 - 3202
(2007/10/03)
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